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Travison, TG, AB Araujo, AB O’Donnell, V Kupelian, JB McKinlay.
2007. A population-level decline in serum testosterone levels in
American men. Journal of Clinical Endocrinology and Metabolism OSF Home
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92:196–202.
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In one of the largest study of its   Broad trends
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population-wide decline in   Disease resistance
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levels during the last 20 years that   Mixtures and synergy
is not related to normal aging or to   Ubiquity of exposure
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health and lifestyle factors known   New exposures
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They found that testosterone    Results
concentrations dropped about 1.2%
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per year, or about 17% overall,
from 1987 to 2004. The downward News/Opinion
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population and in individuals over Useful Links
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increases in testicular cancer, Talk to us: email
hypospadias and cryptorchidism.

The strongest association was

observed in same-aged men from
different sampling years. For
example, a 65-year-old in 2002 had
lower testosterone levels than a
65-year-old in 1987.

Lower concentrations of
testosterone can increase a man’s
risk for age-related diseases,
depression and infertility.

Also, the younger and older men in the study experienced similar
hormone declines that dropped faster than would be predicted by
normal aging.

Context: In men, the hormone testosterone guides behavior and

reproduction. It controls growth and development of sex organs
and other typically male characteristics, such as facial hair and a
deep voice.

Normally, levels fluctuate from conception through puberty then

level out during adulthood before declining as men age. Some
chronic health problems typically seen in older adults, such as
diabetes, depression and obesity, are associated with lower
testosterone levels.

Recent studies have that found environmental impacts on

testosterone levels. For example, testosterone levels were lower
in US Air Force veterans exposed to dioxins while spraying Agent
Orange during the Vietnam War, as well as in men exposed to
phthalates at work.

What did they do?

 Travison et al. used blood hormone data and personal information
collected from men living in Boston, MA, as part of the
Massachusetts Male Aging Study (MMAS). The MMAS examined
men’s health and endocrine function. Data were gathered during
three home visits from 1987-89 (T1), 1995-97 (T2), and 2002-04
(T3). Total testosterone (TT) and serum sex hormone-binding
globulin were measured in the blood and available testosterone
(BT) was calculated. The men self-reported such things as basic
demographics, health status, and smoking and alcohol use.

In this study, Travison et al. analyzed data from 1,532 men

(1,383, 955, and 568, respectively, from T1, T2 and T3) that met
age and birth year requirements. Participants ranged from 45 to
79 years old and were born between 1916 and 1945. The
researchers excluded high and low T levels, missing data, and
unidentified prostate cancer treatment. Within the sample, they
calculated and compared three separate but related associations
among concentration, age, and time. They looked at changes in
testosterone concentrations in the group of men at different
years and ages associated with T1, T2, and T3; testosterone
declines in individual men as they aged during the study; and
testosterone concentrations of men of the same age but in
  different years (age-matched).  

What did they find?

Travison et al. found

strong evidence of a
decline of more than
1% per year in men’s
blood testosterone
 
levels during the last
two decades. The graph
to the right shows  
average levels for each
for men of different
ages in each of the
three measurement
periods (T1-T3).
Dotted lines are 95% confidence
bands. Adapted from Travison et
al.

The first comparison to make is that within a cohort, older men

tend to have lower testosterone levels. Compare, for example, 80
yr old men in T3 compared to 60 yr old men.

The crucial comparison to make is from one cohort to the next,

comparing men of the same age. For example, 60 yr old men
during the first measurement period (red line, 1987-1989) had
total testosterone levels over 500 ng/dL. Men aged 60 yrs old in
the third cohort (blue line, measured 2002-2004) had TT below
450 ng/dL. There is no overlap between the confidence bands of
T1 vs T3: T3 (measured 2002-2004) is always lower than T1.

The trend holds regardless of the men’s age. Similar declines over
the 17 years were seen in all ages of men in the study.

Travison et al. note that the decline within the cohorts related to
age is less than the decrease observed across cohorts. For
example, men aged 70 in T1 had TT only 6% less than men aged
45 in the same cohort. But 60 yr old men in T3 had TT
concentration approximately 13% lower than men the same age
in T1.

To illustrate this point another way, Travison et al. compared the

average decline of testosterone levels in T1 vs T2 as a function
of age, and then contrast that with differences in testosterone
between men of the same age in T1 vs T2. Note that T1 and T2
were only separated by 9 years. The average declines in T1 and
T2 per decade of life were 17 and 20 ng/mL, respectively. But 65
yr old men in T2 had total testosterone levels 50 ng/mL lower
than those in T1, even though the samples were separated by
less than a decade.

Travison et al. then estimated the decline over time, from the
first cohort to the third, for men of the same age (what they
called the age-matched decline). They found that testosterone
 declined by 1.2% per year (95% CI 1.0% to 1.4%).

Bioavailable testosterone (BT) also showed similar declines over

time. The strongest associations again held for age-matched
trends with declines of 1.3% per year (95% CI 1.7% - 1.1%).

None of the health and lifestyle factors examined were

associated with either age-matched declines in either TT or BT:
The age-matched declines remained essentially the same after
controlling for chronic illness, general health, medications,
smoking, body mass index, employment, marital status, and
  other indicators.  

Finally, the trends held when analyzing the data in a number of

different ways, including by interview date, study cohort,
restricting to men of certain ages or birth cohorts, and
considering incomplete versus complete data.

What does it mean?

Travison et al. find that testosterone levels declined in

Massachusetts men by approximately 1.2% per year from the late
1980s through 2004, controlling for the age of the men and other
possible confounding variables.

This study is important because of its large sample size and long
duration. Few studies have looked directly at testosterone levels
over time.

The results are surprisingly consistent with another set of long-

term human epidemiology studies. Those studies also show a
long-term decline in male reproductive functions, such as
decreased sperm health and increased infertility, which are highly
associated with or controlled by testosterone and other androgen
hormones. The rate of decline reported in this study is roughly
comparable to the rate of decline of sperm count reported first by
Carlson et al. in 1992 and then reanalyzed by Swan et al.in 2000.

In commentary accompanying Travison et al.'s study in the

Journal of Clinical Endocrinology and Metabolism, Dr. Shalender
Bhasin (Boston Medical Center) writes: The data in this study are
"important because they provide independent support for the
concerns raised earlier about the reproductive health of men." ...
"it would be unwise to dismiss these reports as mere statistical
aberrations because of the potential threat these trends-- if
confirmed-- pose to the survival of the human race and other
living residents of our planet."

 
 

 
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1375

The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 196-202 This Article
Copyright © 2007 by The Endocrine Society
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Thomas G. Travison, Andre B. Araujo, Amy B. O’Donnell, Varant Kupelian and
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Male Endocrinology

   Abstract 
  Top
Context: Age-specific estimates of mean testosterone (T) concentrations appear to vary by year of Abstract
Introduction
observation and by birth cohort, and estimates of longitudinal declines in T typically outstrip cross- Subjects and Methods
sectional decreases. These observations motivate a hypothesis of a population-level decrease in T over Results
Discussion
calendar time, independent of chronological aging. References

Objective: The goal of this study was to establish the magnitude of population-level changes in serum T concentrations and the
degree to which they are explained by secular changes in relative weight and other factors.

Design: We describe a prospective cohort study of health and endocrine functioning in randomly selected men of age 45–79 yr. We
provide three data collection waves: baseline (T1: 1987–1999) and two follow-ups (T2: 1995–1997, T3: 2002–2004).

Setting: This was an observational study of randomly selected men residing in greater Boston, Massachusetts.

Participants: Data obtained from 1374, 906, and 489 men at T1, T2, and T3, respectively, totaling 2769 observations taken on
1532 men.

Main Outcome Measures: The main outcome measures were serum total T and calculated bioavailable T.

Results: We observe a substantial age-independent decline in T that does not appear to be attributable to observed changes in
explanatory factors, including health and lifestyle characteristics such as smoking and obesity. The estimated population-level declines
are greater in magnitude than the cross-sectional declines in T typically associated with age.

Conclusions: These results indicate that recent years have seen a substantial, and as yet unrecognized, age-independent population-
level decrease in T in American men, potentially attributable to birth cohort differences or to health or environmental effects not
captured in observed data.

   Introduction 
  Top
CONSIDERABLE LOSS OF serum testosterone (T) is thought to be a feature of male chronological Abstract
Introduction
aging (1, 2, 3, 4, 5, 6, 7, 8, 9). Low-serum T has been associated with numerous age-related adverse Subjects and Methods
health conditions including abdominal obesity, diabetes, and prediabetic states (such as insulin resistance, Results
Discussion
impaired glucose tolerance, and metabolic syndrome), dyslipidemia, low bone and muscle mass, impaired References
sexual function, depressed mood, frailty, and decreased quality of life (10, 11, 12). T decline across the
life span therefore represents an issue of great concern for public health, but large studies of within-person decreases in T are rare.

A previous analysis of baseline (T1: 1987–1989) and initial follow-up (T2: 1995–1997) data from the Massachusetts Male Aging
Study (MMAS) indicated that the mean longitudinal (within-subject) decline in serum total T (TT) per year of aging was more than
twice the baseline cross-sectional decrease in mean TT per year of age (13). Qualitative comparisons of other existing studies
likewise indicate that longitudinal decline within subjects is generally of greater magnitude than corresponding cross-sectional trends.
We have hypothesized (13) that this disparity may be attributable to rapid intrasubject declines in health among subjects enrolled in
longitudinal studies. A competing hypothesis, however, asserts that a population-level decline in T concentrations confounds cross-
sectional and longitudinal estimates of T decline with age. A population-level decrease in serum T levels could accelerate the
longitudinal declines in T concentrations typically associated with subjects’ aging and compress cross-sectional decreases associated
with age. Completion of the latest follow-up wave of MMAS data collection (T3: 2002–2004) allows us to investigate formally the
possibility of an age-independent decline in serum T levels with calendar time.

To our knowledge, there exist no extensive published studies of changes in the age-matched distribution of T over time, but a
population-level decline in serum T concentrations would be consistent with evidence of secular decreases in male fertility and sperm
count (14, 15). In this analysis, we estimated differences in serum total testosterone and calculated bioavailable T (BT)
concentrations obtained from individuals of like age observed at different times (e.g. comparing TT in men who were 65 yr old in
1988 to those in comparable men who were 65 yr old in 2003). Our working hypothesis was that age-independent differences
would be attributable to population-level changes in health and lifestyle observable during the nearly 20 yr of study follow-up.

   Subjects and Methods 
  Top
The MMAS is a prospective cohort study of men’s health and endocrine function. Its design and prior Abstract
Introduction
results are described elsewhere (1, 5, 13, 16). Briefly, from a randomly chosen sample of 1709 men living Subjects and Methods
in and around Boston, blood samples and interview data were obtained during in-home visits by trained Results
Discussion
staff, with data collection comprising a baseline (T1) and two follow-up (T2, T3) waves. All study References
activities, including informed consent protocol, were approved by the Institutional Review Board of the
New England Research Institutes.

T concentrations are subject to systematic variation due to components of study design (17, 18, 19). Accordingly, the MMAS took
steps to minimize design bias. To counteract the effects of episodic secretion of hormones, two samples were obtained at each visit
and pooled in equal aliquots at the time of assay. To control the effects of diurnal variation in hormone concentrations (20), samples
were obtained within 4 h of subjects’ waking. Blood was kept in an ice-cooled container for transport and centrifuged within 6 h.
Serum was stored in 5-ml scintillation vials at –20 C, shipped to the laboratory within 1 wk by same-day courier, and stored at –70
C until the time of assay. All hormone values were obtained by a single technician at the Endocrine Laboratory, University of
Massachusetts Medical Center, under the direction of Christopher Longcope, M.D. TT concentrations were obtained by RIA
(Diagnostic Products Corp., Los Angeles, CA). T1 assays were performed in 1994, whereas T2 and T3 samples were assayed
soon after in-home visits. TT inter-assay coefficients of variation were 8.0, 9.0, and 8.3 at T1, T2, and T3, respectively. TT
concentrations obtained in the MMAS fall near the center of the distribution of concentrations obtained in other major epidemiologic
studies (16), and quality-control testing indicated negligible change in concentrations between T1 and T2 due either to sample
storage or assay drift (5).

SHBG was measured using RIA kits at T1 and T2, and at T3 by chemiluminescent enzyme immunometric assay using the
Diagnostics Products Corp. (Los Angeles, CA) Immulite technology. SHBG interassay coefficients of variation were 10.9, 7.9, and
3.0% at T1, T2, and T3, respectively. BT was calculated using the mass action equations described by Södergard et al. (21), with
association constants taken from Vermeulen et al. (22).

Covariate data

Demographic characteristics (age, education, income, marital status), health conditions (cancers, diabetes, heart disease,
hypertension, and ulcer), self-assessed general health (a five-point ordinal scale), and smoking and daily alcohol consumption (23)
were obtained via self-report. Self-reported diagnoses of prostate cancer were supplemented with examination of available medical
records. Height, weight, and waist and hip circumferences were obtained using methods developed for large-scale epidemiological
field work (24). Body mass index and waist-to-hip ratio were derived by calculation. A comprehensive inventory of all prescription
medications used by subjects was obtained. Daily caloric intake was measured using the Willett 1-yr food frequency questionnaire
(25). Physical activity and energy expenditure were derived from subjects’ 7-d recall of duration and frequency of their activities
(26). Depressive symptoms were measured using the Center for Epidemiologic Studies–Depression scale (27).

Analysis sample
To enhance comparability of age distributions across study waves and to allow for analyses of T concentrations by subjects’ birth
cohorts, data were restricted to observations obtained on men of age 45–79 yr born between 1916 and 1945, inclusive. This
yielded potential samples of 1399, 975, and 579 observations at T1, T2, and T3, respectively. Of these, we excluded all
observations on the seven men who had T1 serum total T less than 100 ng/dl (3.5 nmol/liter), and two outlying observations with
total T more than 1200 ng/dl (41.6 nmol/liter). One hundred twenty-six observations were excluded because they were taken on
subjects who, before the relevant study wave, had a diagnosis of prostate cancer, for which treatment via hormone suppression
therapy could not be ruled out. An additional 44 observations were excluded because subjects lacked complete health data. This
yielded samples of 1374, 906, and 489 observations at T1, T2, and T3, respectively, totaling 2769 observations taken on 1532
men.

Statistical analysis

Exploratory analyses were conducted to assess the functional form of associations. We used mixed-effects linear regression (28)
with random subject-level intercepts and slopes to estimate trends and test hypotheses. Hormone concentrations were log (base e)
transformed to remove any effects of the mild skew in the data. For a covariate with associated regression estimate ß*, we 
approximated the corresponding percent change in mean hormone concentrations using the quantity 100 x (eß *-1). Results were
considered statistically significant if null hypotheses could be rejected at the 0.05 level. The significance of effects was evaluated using
Wald and likelihood ratio tests. Confounders were used in multivariate models if they had considerable theoretical importance or
were significantly associated with T concentrations in the presence of other predictors. All confounders were allowed to vary with
time and were treated as internal time-dependent covariates (29).

   Results 
  Top
A description of the analysis sample is given in Table 1 . Median baseline age was 58 yr, with Abstract
Introduction
interquartile range 52–64 yr. Seven hundred nineteen (52%) subjects reported at least one chronic illness, Subjects and Methods
340 (25%) were current smokers, 296 (22%) were obese (body mass index 30), and 300 (22%) Results
Discussion
reported use of at least three prescription medications. Over the course of study follow-up, we observed References
marked increases in the proportion of subjects reporting at least one chronic illness or who were
overweight or obese, as well as in the number of medications being used by subjects; there were dramatic decreases in the
proportion of subjects who were current smokers or who were employed.

View this table: TABLE 1. Descriptive statistics by MMAS study wave, mean (SD), or count (%)
[in this window]
[in a new window]

 
 
Table 2 presents descriptive statistics for age and T concentrations at all study waves. Median TT at baseline was 501 ng/dl (17.4
nmol/liter), with interquartile range 392–614 ng/dl (13.6–21.3 nmol/liter); the corresponding values at T3 were 391 ng/dl (13.6
nmol/liter) and 310–507 ng/dl (10.7–17.6 nmol/liter). Among subjects on whom follow-up data could be obtained, the median lag
time between observations at T1 and T2 was 8.8 yr, and between T2 and T3 was 6.4 yr.

View this table: TABLE 2. Total and calculated bioavailable T concentrations, by study wave and corresponding age
[in this window] range
[in a new window]

 
 
Exploratory analyses

We used graphical displays to assess three interrelated quantities: first, the cross-sectional association between T concentrations and
age at any study wave; second, the longitudinal decline of T over time associated with subjects’ aging; and third, the age-matched
difference between, for instance, mean T concentrations obtained from 65-yr-old men in 1988 and concentrations obtained from 65-
yr-old men in 2003 (equivalently, we sought to compare T concentrations obtained in 1988 from men born circa 1923 to
concentrations obtained in 2003 from men born circa 1938). A depiction of mean TT concentrations is given in Fig. 1 , which
displays nonparametric locally weighted estimates of TT by age separately for each study wave. The negative slopes of the wave-
specific fits correspond to the relatively modest cross-sectional decline of mean TT with age. The age-matched difference by time
(denoted by the vertical distance between the fitted curves in overlapping age ranges) is likewise evident. The data suggest that the
cross-sectional decline of TT within T1 is smaller than the age-matched difference between concentrations taken at T2 vs. T1, which
are separated by only approximately 9 yr in time; simple linear regression estimates indicate cross-sectional TT decreases of 17 and
20 ng/dl (0.6 and 0.7 nmol/liter) per 10 yr of age at T1 and T2, respectively, whereas the mean difference between subjects age 65
at T1 vs. subjects age 65 at T2 is approximately 50 ng/dl (1.7 nmol/liter).
 FIG. 1. Crude mean TT concentrations, by MMAS study wave (T1, T2, T3) with
confidence bands (dotted lines). Estimates are obtained from a generalized additive
model with a lowess smoothing term.

View larger version (14K):

[in this window]
[in a new window]

 
 
To explore more carefully trends associated with age and time, it is useful to depict subjects by birth cohort. Figure 2 displays all
(log-transformed) TT concentrations in the analysis sample vs. age and includes mixed-effects regression (28) estimates of the
average within-subject TT decline by 5-yr birth cohort. A display fitting nonparamentric locally weighted regression smooths (not
shown) was similar. We refer to 5-yr birth cohorts as cohort I (men born in the years 1916–1919), cohort II (1920–1924), and so
on, to cohort VI (1940–1945). Although the design of the MMAS precludes all cohorts from being observed over all ages, the
pattern of decreasing TT concentrations across adjacent cohorts is compelling. That the regression lines are approximately parallel
indicates that the age-matched decline over time (again indicated by vertical distances between pairs of fitted lines) is consistent
across age groups.

FIG. 2. MMAS mean TT vs. age, by 5-yr birth cohort. Fitted lines are obtained from
cohort-specific mixed-effects regression of the log of TT on centered age, with
random effects for each subject. Data points in the analytic sample are also depicted;
each subject contributes up to three observations. Models are fit using maximum
likelihood.

View larger version (27K):

[in this window]
[in a new window]

 
 
Detailed exploratory analyses provide additional evidence of an age-matched time trend. Table 3 provides an illustrative example.
Here we restrict our attention to cohorts II and IV and their associated TT concentrations at T1 and T2. Calculation indicates that,
among subjects in cohort IV (born 1930–1934), the proportionate decline in mean TT from T1 to T2 was 16.1% (the median age at
T1 was 56 yr and at T2 was 64 yr). By contrast, a cross-sectional comparison at baseline indicates that cohort II (median age 65 yr)
T levels are only 5.5% lower than those of cohort IV (median age 56 yr). The age-matched time difference (comparing observations
on men of similar age separated by time: cohort IV at T2 vs. cohort II at T1) is approximately 11.2%, approximately the difference
between the cross-sectional and longitudinal trends. Similar effects may be observed in other combinations of birth cohorts and study
waves.

View this table: TABLE 3. Age-matched trends: illustrative example

[in this window]
[in a new window]

 
 
Formal results: total T

An analysis of all data yields results in agreement with our exploratory observations. To estimate cross-sectional and longitudinal
trends, we partition subjects’ ages into two pieces: age at baseline and subsequent aging, the latter defined as calendar time since
study entry. The per-year age-matched time trend was estimated as the difference between the associated longitudinal and cross-
sectional regression estimates (30, 31, 32). Mean cross-sectional, longitudinal, and age-matched trends derived from mixed-effects
models of TT as a function of age and aging are depicted on the left side of Table 4 . The estimated cross-sectional decline in TT is
–0.4% per year of age, with a corresponding 95% confidence interval (CI) of (–0.6%, –0.2%). The longitudinal within-subject
decline is approximately –1.6% per year (CI: –1.8%, –1.4%). The age-matched time trend is –1.2% per year (CI: –1.4%, –1.0%).

View this table: TABLE 4. Longitudinal regression results

[in this window]
[in a new window]

 
 
We hypothesized that the presence of the age-matched time trend could be accounted for by observable secular changes in health
status or lifestyle characteristics. This hypothesis relies upon an assertion that for men of, for example, 65 yr of age, health/lifestyle
characteristics vary by observation time. For instance, the well-known and ongoing secular increase in obesity might explain the fact
that the typical blood sample taken from a 65-yr-old man in 2003 exhibited lower TT concentrations than a sample taken from a
different 65-yr-old subject in 1988 (the latter subject having been born approximately 15 yr earlier than the former). In this analysis
we observed little evidence of age-independent trends with respect to most covariate factors; notable exceptions to this rule,
however, were the aforementioned increases in relative weight, as well as population-level changes in the prevalence of smoking and
the concurrent use of multiple medications (polypharmacy). There were substantial age-specific increases in obesity and
polypharmacy over the course of study follow-up, whereas the proportion of subjects who smoked cigarettes declined dramatically
in all age groups. These trends are potentially important in accounting for an apparent secular decline in TT levels, because weight
gain, smoking cessation, and the use of medications have been associated with decreases in serum T (33, 34, 35, 36, 37). However,
although controlling for these and other factors significantly associated with TT concentrations was sufficient to substantially decrease
the estimates of cross-sectional and longitudinal decline in TT, the estimate of the age-matched time trend was only slightly reduced
(see Table 4 ). Results were essentially unchanged when all covariate effects (see Subjects and Methods) were included in
multivariate analyses.

Bioavailable T

As noted, the technology by which SHBG was measured at T1 and T2 (RIA) differed from that employed at T3 (Immulite).
Because of this, observed variation in calculated BT concentrations between T2 and T3 could be artificially inflated. We therefore
restricted formal estimation of cross-sectional, longitudinal, and age-matched time trends in BT to values obtained at T1 and T2.

In the resulting models, as is consistent with other published results, cross-sectional and longitudinal age trends in BT were
substantially sharper than those in TT. However, the age-matched time trend was similar in magnitude to that in TT and was likewise
robust to control for all covariates. When only the effects of age and aging were controlled, the estimated age-matched time trend in
BT values was approximately –1.4% per calendar year (95% CI: –1.8%, –1.1%), whereas when the effects of all other covariates
were accounted for, the estimated age-matched trend was –1.3% per year (95% CI: –1.7%, –1.1%).

Sensitivity analyses. To test the robustness of all findings, we performed a number of additional analyses. Analyses including effects
for town of residence, assay batch, month of interview, and time of study visit yielded results nearly identical to those described
above. Results did not change substantially when analyses of TT were restricted to data from any two of the three study waves.
Likewise, results were similar when analyses of either TT or BT were restricted to men above or below certain ages, to men with
complete data at all three waves, or to men in particular birth cohorts. In addition, we examined the distribution of baseline TT and
BT concentrations among those subjects who had complete data vs. those who did not and found that they were comparable.

   Discussion 
  Top
These findings indicate that the past 20 yr have seen substantial age-independent decreases in male serum Abstract
Introduction
T concentrations, decreases that do not appear to be the consequence of the contemporaneous trends in Subjects and Methods
health and lifestyle considered here. It remains unclear to what these apparent population-level decreases Results
Discussion
in T are attributable. References

Because age, birth year, and observation time are perfectly confounded (that is, knowledge of any two determines the third), their
influences are not separable through data analysis. Age-matched time differences cannot, therefore, be definitively attributed to
historical (prestudy) trends affecting different birth cohorts in different ways or, rather, to contemporary secular changes in the
underlying population (e.g. to age-independent increases in obesity beyond those captured in the analyses described here). As noted
previously, there is little evidence that the association between T and age (that is, the slope of a line depicting the relationship
between the two) depends on birth year, so that irrespective of birth cohort, decreases in T with age are constant (see Fig. 2 ). This
evidence is consistent with, but does not prove, the notion that the linear T/age association is consistent across different generations
and implies that the age-matched declines in T levels associated with each year of calendar time apply equally to men from 45 to 80
yr of age.

The presence of the age-matched trend itself, however, suggests that neither cross-sectional nor longitudinal investigations may
properly describe the true effect of aging per se on T (30, 31, 32). Suppose, for instance, there were an unmeasured but persistent
environmental exposure associated with decreased T levels, affecting recent generations of men at birth. In that case the cross-
sectional decline in T with age might be underestimated, because younger men could have lower T levels than their historic
counterparts and appear more like their older contemporaries (born before the advent of the exposure) than one would normally
expect in the absence of such a hypothetical exposure.

On the other hand, if the age-matched trend is not historic but rather indicative of population-level changes occurring during the time
subjects were under study, the age-matched trend denotes a secular trend in T concentrations over that time. Under this scenario it is
easy to see that longitudinal estimates of change in T concentrations may in fact overstate the true effect of aging, because the
observed effect of a year of aging would include not only the true age-related decreases in T but also whatever decreases the
population-level secular trend imposed on all men simultaneously. Such a secular trend in T might be attributable to parallel
population-level changes in the distribution of health and lifestyle factors, independent of age. We have observed, however, that
although baseline and evolving health states in the study sample successfully account for a substantial proportion of the cross-
sectional and longitudinal associations between age and T, they do not explain the age-matched decline in T concentrations.

We therefore hypothesize that the observed age-matched decline in serum testosterone is due to some undocumented historical or
contemporary influence, health-related or environmental, which manifests in observable age-matched differences in T concentrations
separated either by time of observation or by birth cohort.

It is interesting to note that the estimated age-matched time trends in TT and BT are of comparable magnitude. This may not in itself
be surprising, because the time trends are explicitly intended to remove the effects of aging itself, leaving only secular changes in other
factors as contributors to changes in T levels with time. We can currently offer, however, no additional speculation as to whether one
would expect a secular trend in BT to differ markedly from that in TT.

Some limitations of this study should be acknowledged. Though the consistency of the methods by which TT concentrations were
obtained, as well as that of the age-matched time trend across all pairs of study waves, indicates that design artifacts are likely not
the cause of these observations, they cannot be completely discounted as contributors to the age-matched time trends, because
relatively subtle changes in measurement may contribute substantially to differences between observations separated by time.
Likewise, though the evidence suggests that subject loss to follow-up has not influenced our result, we must acknowledge the
possibility of biases arising from subject dropout. However, under the assumption of such a survival bias, those subjects who
remained in the study, being younger (and presumably more healthy) than those lost to follow-up, would be likely to exhibit higher
mean T concentrations during follow-up than would the complete sample had it been fully observed. In such a scenario, it is likely
that the estimates of longitudinal and age-matched decline described here would be too low, rather than too high.

An added concern is that the covariates considered in this analysis cannot account for all known causes of T decline. Indeed, it is
exceedingly unlikely that population-level T concentrations would decline with calendar time, independently of age, of their own
accord. Rather, if such declines exist, they have one or several causes that themselves may be evolving over time. We have observed
that several candidate causes observable at the level of the individual subject, most notably the well-known secular declines in
smoking rates and increases in relative weight, do not appear to explain completely the observed age-matched trends in T. It remains
possible, however, that more detailed and comprehensive measurement of such factors could fully account for the age-matched
trends in T.

If the trends observed in the MMAS are real and continue, the prevalence of low T in American men will exhibit increases in excess
of those to be expected given the projected aging of the population (38). As such, it is important that future research endeavors to
confirm or disprove the existence of age-independent T declines and to discover their causes, environmental or otherwise, so that
they may be addressed through prevention.

   Acknowledgments 
 
The authors thank Dr. Don Brambilla for helpful discussions and also acknowledge the many contributions of Dr. Christopher
Longcope, who passed away in 2004. For nearly 20 yr, he was an indispensable colleague on the Massachusetts Male Aging Study.
His scientific expertise and collegiality are missed.

   Footnotes 
 
This work was supported by the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases:
DK44995, DK51345; National Institute on Aging: AG04673).

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 24, 2006

Abbreviations: BT, Bioavailable testosterone; CI, confidence interval; MMAS, Massachusetts Male Aging Study; T, testosterone;
TT, total T.

Received June 27, 2006.

Accepted September 25, 2006.

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